4-Fluoropyrrolidine derivatives are particularly useful for medicinal applications and have been utilized in the development of therapeutics such as dipeptidyl peptidase (DPP) IV inhibitors, which serve for diabetes treatment etc. [see, for example, Bioorganic & Medicinal Chemistry, 2008, Vol. 16, pp. 4093-4106 (Taisho Pharm.); Bioorganic & Medicinal Chemistry Letters, 2007, Vol. 17, pp. 4167-4172 (LG Life Sci.); WO 03/002533 A2 (Smithkline Beecham); WO 2004/020407 A1 (Taisho Pharm.); WO 2004/009544 A1 (Yamanouchi Pharm.); Jpn Kokai Tokyo Koho JP 2004-244412 (Kotobuki Pharm.); WO 2005/075421 A1 (Kyorin Pharm.); WO 2006/043595 A1 (Astellas Pharm.); WO 2006/134613 A2 (Aurigene Discovery Tech.); WO 2008/001195 A2 (Glenmark Pharm.)], and peptide deformylase (PDF) inhibitor which is a novel class of antimicrobial agents [Organic Process Research & Development, 2008, Vol. 12, pp. 183-191 (Novartis Pharm.)]. However, there are a number of drawbacks in the conventional preparation of 4-fluoropyrrolidine derivatives, as is discussed more fully below.
For example, (2S,4S)-4-fluoropyrrolidine-2-carboxamide, its salts and N-protected derivatives (compounds F and G are shown in Scheme 1, below), are significant intermediate compounds for the preparation of DPP inhibitors [see, for example, Bioorganic & Medicinal Chemistry, Vol. 16 (2008), pp. 4093-4106 (Taisho Pharm.); WO 03/002533 A2 (Smithkline Beecham); Jpn Kokai Tokyo Koho JP 2004-244412 (Kotobuki Pharm.); WO 2006/134613 A2 (Aurigene Discovery Tech.); WO 2008/001195 A2 (Glenmark Pharm.); Jpn. Kokai Tokkyo Koho JP 2008-239543 (Kyorin Pharm.)]. The compounds F and G have been prepared as shown in Scheme 1, according to the literature [See WO 03/002553 A2 (Smithkline)]. A starting material, (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (called as trans-4-hydroxy-L-proline) (compound A), is commercially available, isolated from gelatin (collagen). Compound A was (i) esterified, followed by (ii) N-substitution (N-protection), giving compound C (R=a protecting group) which was then, (iii) fluorinated with diethylaminosulfur trifluoride (DAST) to give compound D. Next, step (iv) was a careful hydrolysis of compound D with lithium hydroxide because of possible racemization, and in steps (v) and (vi) transformation of compound E to compound F, which consisted of two steps; a reaction step with di-tert-butyldicarbonate followed with ammonium hydrogen carbonate. N-Deprotection reaction of compound F gave compound G.

(2S,4S)—N-haloacetyl-4-fluoropyrrolidine-2-carboxamide, compound K shown in Scheme 1, is another important useful intermediate for the preparation of DPP IV inhibitors [see, for example, with regard to DPP IV inhibitors: WO 2007/113634 A1 (Matrix Laboratories, Ltd.); U.S. Pat. No. 7,186,731 B2 (Astellas Pharma Inc.); WO 2005/042533 A2 (Fujisawa Pharmaceutical CO, Ltd.); WO 2003/074500 A2 (Sanofi-Synthelabo)]. Compound K was prepared by step (xii), haloacetylation of compound G, which was therefore ultimately prepared from starting material compound A via a total of 8 steps, as shown in Scheme 1.
(2S,4S)—N-haloacetyl-4-fluoropyrrolidine-2-carbonitrile, compound L shown in Scheme 1, is another important intermediate for the preparation of the DPP IV inhibitors. Compound L was prepared by step (xiii), dehydration of compound K, as shown in Scheme 1.
N-protected (2S,4S)-4-fluoropyrrolidine-2-(N-methyl-N-methoxy)carboxamide, compound H shown in Scheme 1, is another useful intermediate for the preparation of DPP IV inhibitors [Bioorganic & Medicinal Chemistry Letters, 2007, Vol. 17, pp. 4167-4172; Organic Process Research & Development, 2008, Vol. 12, pp. 626-631]. Compound H was prepared by steps (viii) and (ix), a two-step transformation of compound E to compound H, as shown in Scheme 1 above.
(2S,4S)-4-Fluoropyrrolidine-2-carbonitrile, its salts and N-protected derivatives (compounds I and J shown in Scheme 1), are also useful intermediate compounds for the preparation of DDP IV inhibitors [see, for example, WO 03/002533 A2 (Smithkline Beecham); WO 2008/001195 A2 (Glenmark Pharm.); and Jpn. Kokai Tokkyo Koho JP 2008-239543 (Kyorin Pharm.)]. As shown in Scheme 1, the compound I was prepared by dehydration of compound F, and compound J was prepared by deprotection of compound I.
Alternatively, (2S,4S)-4-fluoropyrrolidine-2-carbonitriles compounds I and J were prepared as shown in Scheme 2 according to the literature [WO 03/002533 A2 (Smithkline Beecham)]. Thus, compound A was N-protected in step (xiv), followed by steps (xv) and (xvi), transformation of compound M to compound N (two steps; reaction with di-tert-butyldicarbonate and then with ammonium hydrogen carbonate); then step (xvii) dehydration of compound N with trifluoroacetic anhydride and pyridine, and step (xviii) fluorination of compound O with DAST, giving compound I. N-deprotection of compound I gave compound J.

According to the literature [WO 2008/001195 A2 (GlenMark Pharm.)], compound I was also prepared from compound N via step (xx), O-substitution (O-protection). Step (xxi) is a dehydration of compound P with POCl3, imidazole, and pyridine, and step (xxii) O-deprotection of compound Q with ammonia gas, and finally step (xxiii) fluorination of compound O with DAST, as shown in Scheme 3.

There are a number of significant drawbacks to these conventional methodologies in the production of fluorinated intermediate compounds. These conventional methodologies require a large number of stereospecific chemical transformations for the preparation of the intermediates, which significantly reduces overall yield, thereby increasing cost and time. In addition, these processes required tedious purification steps.
As such, problems with production methods for the fluorinated intermediate compounds herein have made it difficult to prepare useful, highly pure therapeutics in a cost effective and timely fashion. Therefore, there is a need in the art for a methodology which makes it possible to prepare fluorinated intermediates easily and cost effectively. The present invention is directed toward overcoming one or more of the problems discussed above.
As will be more fully described below, the present inventors have developed a stereospecific double fluorination of 4-hydroxypyrrolidine-2-carboxylic acid compounds. Embodiments of the invention significantly decrease the necessary reaction steps, and in addition, attain highly pure products through highly stereospecific reactions. Thus, the compounds and processes of the present invention provide a novel, relatively easy and cost effective method for the preparation of highly pure fluorinated intermediates useful for therapeutics such as DDP IV inhibitors. Embodiments herein provide a significant and unexpected improvement over the state of the art.